Chronic ethanol (EtOH) exposure and AIDS exposure are known to cause cardiomyopathy, and to act synergistically when combined. Moreover, both ethanol and AIDS exposure have been observed to inhibit mitochondrial function, alter mitochondrial structure, and increase oxidative stress. Inhibition of mitochondrial oxidative phosphorylation reduces mitochondrial energy production and increases mitochondrial reactive oxygen species (ROS) generation, which have been linked to hypertrophic cardiomyopathy and dilated cardiomyopathy, respectively. Therefore, we hypothesize that both ethanol and AIDS exposure induce cardiomyopathy by reducing mitochondrial energy production through the direct disruption of OXPHOS and the indirect inhibition of OXPHOS by mitochondrial ROS. To test this hypothesis, we propose to challenge mice harboring various genetic defects in mitochondrial energy production and ROS detoxification to chronic ethanol, murine AIDS (MAIDS), and ethanol plus MAIDS exposure. The four strains will include (1) wildtype mice, (2) mice deficient (-/-) in the mitochondrial heart-muscle isoform of the adenine nucleotide translocator (ANT1), (3) mice partially deficient (+/-) in the mitochondrial Mn superoxide dismutase (MnSOD), and (4) mice deficient (-/-)in the glutathione peroxidase (GPx). The ANTI-defect reduces mitochondrial ATP availability to the heart and predisposes to hypertrophic cardiomyopathy. The MnSOD-defect increases mitochondrial ROS production and leads to dilated cardiomyopathy. The GPx1 -defect increases cardiac cytosolic hydrogen peroxide levels and increases the potential for viral myocarditis. Control, ethanol, MAIDS, and ethanol + MAIDS exposed mice will then be analyzed for cardiac pathology, changes in cardiac mitochondrial OXPHOS, increased cardiac oxidative damage, and alterations in the expression of mitochondrial and oxidative stress gene expression. If the ANT -/- animals develop a more severe hypertrophic cardiomyopathy and an increased predilection to dilated cardiomyopathy an ethanol and MAIDS exposure then this will indicate that mitochondrial energy deficiency is important in cardiomyopathy. If the MnSOD +/- animals have an increased frequency of dilated cardiomyopathy, then this will implicate mitochondrial ROS toxicity. If the GPx1 -/- animals have an increased incidence of myocarditis, then this will indicate that cytosolic oxidative stress is important in induced cardiomyopathy.